CHAPTER 15 Breast Cancer
Breast cancer ranks as the leading cause of new cancers in women, accounting for approximately 31% of all cancers in women, compared with about 13% associated with lung and bronchus cancers.1 In 2001, more than 192,000 new cases of breast cancer were diagnosed in American women. In terms of cancer mortality, breast cancer is the No. 2 cause of cancer deaths among women, comprising about 15% of all cancer deaths, second only to lung and bronchus cancers. Despite the overall decline in breast cancer mortality over the past decade, it is estimated that more than 40,000 deaths were attributed to the disease in 2003.
BREAST CANCER RISK
Women often hear that they have a 1 in 8 chance of developing breast cancer. This statement is based on statistics from the National Cancer Institute. If current rates stay constant, a female baby born today has a 1 in 8 chance of having breast cancer during her lifetime.2 These statistics are broken down by age incidence in Table 15-1.
Table 15-1 Chances of developing breast cancer by age group
| AGE GROUP (YR) | INCIDENCE OF BREAST CANCER |
|---|---|
| 30–40 | 1 in 252 |
| 40–50 | 1 in 68 |
| 50–60 | 1 in 35 |
| 60–70 | 1 in 27 |
| Ever | 1 in 8 |
These probabilities are based on population averages. An individual woman’s risk of breast cancer may be higher or lower depending on a variety of factors, including family history, genetic factors, reproductive history (age at menarche, age at first pregnancy, number of pregnancies, breastfeeding), the presence of certain types and features of benign breast disease, and other factors that are not yet fully understood. Non-Hispanic white, Hawaiian, and black women have the highest level of breast cancer risk. Some of the lowest levels of risk are found among Korean and Vietnamese women.3
The incidence of breast cancer has been increasing steadily since 1940, with global breast cancer rates increasing at a rate of approximately 2% per year. Several theories (explained below) have been proposed to explain this trend. Table 15-2 shows statistics for the various risk factors.
Table 15-2 Risk factors for breast cancer*
| RISK FACTOR | RELATIVE RISK |
|---|---|
| Family history of breast cancer | |
| One relative | 1.4 to 2.8 |
| Two relatives | 4.2 to 6.8 |
| Nulliparity | 1.5 to 1.9 |
| First child born after age 30 | 1.9 |
| First menstrual period before age 12 | 1.2 to 1.3 |
| Last menstrual period after age 55 | 1.5 to 2.0 |
| Atypical hyperplasia on previous biopsy | 2.2 to 5.0 |
| Obesity | 1.2 |
| Postmenopausal estrogen replacement therapy | 1.2 to 2.1 |
| Alcohol use | |
| One drink per day | 1.4 |
| Two drinks per day | 1.7 |
| Three drinks per day | 2.0 |
* Many women in whom breast cancer develops do not have any risk factor, other than age.
Genetic Predisposition
The risk for women with a first-degree relative (mother, sister, daughter) who has had breast cancer is 1.4 to 2.8 times greater than that of women with no such family history.4 Gene mutations such as BRCA1, BRCA2, and p53 have been linked to increased breast cancer risk. However, only 10% to 15% of all breast cancer cases appear to be genetically linked.
Dietary Factors
In 1997, the American Institute for Cancer Research and the World Cancer Research Fund concluded that adult diets high in polyunsaturated or monounsaturated fat may have no relationship to breast cancer risk, independent of any contribution to total fat intake, but diets high in saturated fat may increase the risk of breast cancer.5 In a 2003 report published in the Journal of the National Cancer Institute, researchers found that intake of animal fat, mainly from red meat and high-fat dairy foods, during the premenopausal years is associated with an increased risk of breast cancer.6 Postmenopausal obesity and excessive alcohol consumption also appear to increase a woman’s risk of breast cancer. A more detailed discussion of diet is presented later in this chapter.
Environmental Factors
Some researchers believe that prolonged exposure to pesticides, chlorinated solvents, ionizing radiation, and polychlorinated biphenyls (PCBs) contributes to the increased incidence of breast cancer.7 Although evidence implicates organochlorine pesticide residues, this area is difficult to accurately assess and systematically review.8
Early Detection
Mammography has dramatically increased the clinician’s ability to detect breast cancer. Some researchers argue that the incidence of breast cancer has not increased as dramatically as the numbers suggest but that this “increase” is related to increased rates of early detection. These numbers may reflect, in part, increased access and use of mammograms and the education of women in the performance of breast self-examination. However, increased rates of detection on mammography cannot account for all the long-term increase reported in breast cancer rates.9
Lifestyle Factors
Many women have delayed childbearing to a later age or have chosen not to have children, resulting in increased lifetime exposure to unopposed estrogen stimulation. Early age at the time of first pregnancy appears to be strongly protective against breast cancer. Some evidence suggests that late pregnancy actually promotes development of the disease. Breastfeeding also offers a protective effect. The longer a woman breastfeeds and the more babies she nurses, the lower her risk of breast cancer.10 The growing trend toward later childbearing and the use of infant formulas may contribute to the increased incidence of breast cancer among women in industrialized nations.
INTEGRATIVE MEDICINE
Several published reports indicate that women often turn to complementary and alternative medicine (CAM) after receiving the diagnosis of breast cancer (see Chapter 1). A study of predominantly non-Hispanic white women with breast cancer revealed that 64% reported regular use of vitamins and minerals and that 33% regularly used antioxidants, herbs, and health foods. Forty-nine percent of all participants regularly used prayer and spiritual healing, followed by support groups (37%) and humor or laughter therapy (21%). Approximately 27% of all participants used massage at least once after the diagnosis.11 Traditional and ethnic medicine therapies were rarely used.
A survey of the types and prevalence of alternative therapies used by Latino, Chinese, black, and white women with breast cancer revealed that 48% had used at least one type of alternative therapy and approximately 33% had used two or more types after receiving the diagnosis of breast cancer but only 50% discussed this with their physicians. The most popular interventions were dietary therapies (27%), spiritual healing (24%), specialized diets (20%), physical methods (massage and acupuncture) (14%), herbal remedies (13%), psychological methods (9%), and megavitamins (8%). Black women were most likely to use a spiritual approach (36%), and Chinese women were most likely to use herbal remedies (22%). Women who used CAM tended to be younger and better educated, to have more private insurance, and a later stage of cancer at the time of diagnosis. More than 90% said they found alternative therapies helpful and, with the exception of homeopathy, would recommend these therapies to their friends.12
As these surveys suggest, a significant number of women with breast cancer reach out for CAM therapies during the course of treatment, primarily as a supplement to standard medical methods and as a strategy for avoiding passivity and feelings of hopelessness.13 The following is a description of some of the popular remedies currently being recommended for the treatment or prevention of breast cancer.
Diet and Nutrition
High intakes of carotenoids have been associated with a lower risk of breast cancer in several epidemiologic studies. Dietary intake of vitamins A, C, and E; specific carotenoids; and fruits and vegetables were assessed in 83,234 women participating in the Nurses’ Health Study. Consumption of five or more servings of fruits and vegetables per day was associated with a modestly lower risk of premenopausal breast cancer in the cohort as a whole with stronger risk reduction among those with a family history of breast cancer and alcohol consumption.14 A study of women in Shanghai failed to reveal a relationship between breast cancer and total vegetable intake, but it did show declining risk with greater consumption of dark yellow-orange or green vegetables and white turnips. An inverse relationship was found between total fruit intake and breast cancer risk.15
A Canadian cohort study of 56,837 women showed that women who consumed high amounts of fiber had a 30% reduction in breast cancer risk compared with those who consumed low amounts of dietary fiber.16
Research suggests that it is not so much the amount of fat in the adult diet but, rather, the type of fat. The preponderance of evidence indicates that a high consumption of animal fat in the premenopausal years increases the risk of breast cancer. Common sense dictates that women should focus on a diet rich in fruits, vegetables, whole grains, low-fat dairy products, fish, and poultry several times a week and limit consumption of red meat to several times per month. Emphasis should be placed on monounsaturated and polyunsaturated fats, with generous use of olive oil. Although many debate the role of xenoestrogens in the diet, it seems wise to limit exposure to them through the consumption of organically grown foods and the consumption of fewer foods stored in plastic.
Phytoestrogens.
Phytoestrogens in soybeans inhibit breast cancer cell proliferation in vitro and breast cancer development in animal models.17 It is hypothesized that phytoestrogens reduce the risk of breast cancer because their estrogenic activity is relatively weak compared with endogenous estrogens.18 By binding to estrogen receptors in the premenopausal woman, phytoestrogens “turn down” estrogen production through negative feedback at the level of the hypothalamus and pituitary gland. In other words, when endogenous estrogen levels are high, phytoestrogens may have an antiestrogenic activity by preventing estrogen from binding to the estrogen receptor through competitive inhibition.
Other researchers have postulated that the anticarcinogenic effect of isoflavones is due to modulation of estrogen metabolism away from the production of potentially carcinogenic metabolites: 16α-(OH) estrone, 4-(OH) estrone, and 4-(OH) estradiol.19 Genistein, an isoflavone present in many plants including soy and red clover, has been shown to inhibit a liver enzyme in rats that catalyzes the conversion of catechol estrogens to their electrophilic quinines. These compounds may be responsible for the genotoxicity of 4-hydroxylated estrogens.20
Human studies yield conflicting results with regard to shifting estrogen metabolism. A randomized crossover study of 18 postmenopausal women showed that daily consumption of 65 to 132 mg/day of isoflavones decreased the ratio of genotoxic to total estrogens.21 Premenopausal Japanese women consuming a soy milk–supplemented diet for 3 consecutive months demonstrated a decrease in serum estrone and estradiol levels compared with those in the control diet group, although the difference was not statistically significant.22 Another study failed to show any significant change in the duration of menstrual cycles, serum concentrations of sex hormones, or urinary estrogen-metabolite ratio among premenopausal women who supplemented their diets for 2 months with approximately 40 mg total isoflavones.23 This daily dose of isoflavones is lower than the positive trial and may not have been sufficient. If isoflavones do shift urinary estrogen/metabolite ratios, the optimal dose and age for dietary intake remain to be determined.
An estrogen-independent mechanism may also account for some of the purported cancer-preventive effects of phytoestrogens. Genistein has been shown to reduce tyrosine kinase and inhibit angiogenesis.24 Rats exposed to a carcinogen had a 40% lower rate of cancer when they were simultaneously given genistein.25 The findings of in vitro and animal studies suggest that the inhibitory action of genistein on breast cancer cells is complex and only partially mediated by the alteration of estrogen receptor–dependent pathways.
Although preliminary data are intriguing, a recent review of the literature failed to support the hypothesis that a soy-rich diet in adult women is protective against the development of breast cancer, although immigrant and epidemiologic studies do suggest that soy is somewhat protective if consumed in early childhood and adolescence.26 As of early 2003, 13 studies had been conducted to assess the direct relationship between individual adult dietary intake of soy products and the risk of breast cancer. Four of the 13 studies were prospective, and all failed to demonstrate statistically significant reductions in breast cancer. Four studies involved assessment of urinary isoflavone excretion, although three were case-control studies in which excretion was measured after breast cancer occurrence, thus seriously limiting causal interpretation of the results. The only prospective study involving urinary measurements before the occurrence of breast cancer showed a nonsignificant breast cancer risk reduction associated with high urinary excretion of isoflavones.27 Three studies measured enterolactone (lignan) levels; two case-control studies showed a preventive effect with regard to breast cancer, but the only prospective study did not.27 In a prospective population-based cohort study in Japan, frequent consumption of miso soup and isoflavones was associated with a reduced risk of breast cancer. The associations did not change substantially after adjustment for potential confounders, including reproductive and family history, smoking, and other dietary factors.28 Population studies of the relationships between phytoestrogens and cancer are difficult to interpret because of the number of confounding factors. A great deal of complexity and diversity exists among phytoestrogens, making these compounds a challenge for researchers, as in vitro and in vivo studies often yield conflicting results. Specific cellular responses depend on the type of phytoestrogen, the concentration of estrogen receptors, co-activators, co-repressors, and duration of exposure. As one author states, “Overall, it is naïve to assume that exposure to these compounds is always good; inappropriate or excessive exposure may be detrimental.”29
In addition to prevention, many women want to know if phytoestrogens are safe if they have a history of breast cancer. One review found that adult consumption of soy does not appear to affect the risk of breast cancer; nor does soy consumption affect the survival of breast cancer patients.30 Based on in vitro and animal studies, women who enjoy eating soy and other phytoestrogen-rich foods should not be discouraged from consuming them in moderation after being treated for breast cancer. After this review was published, however, one in vitro study31 and one animal study32 demonstrated that genistein inhibits the antiproliferative effect of tamoxifen and increased the expression of estrogen-responsive genes, raising questions about isoflavone use by women undergoing treatment with this antiestrogen drug.
In summary, it appears that phytoestrogen/soy consumption early in life has a protective effect against breast cancer but that consumption later in life may not. Plant-based diets, however, offer many health benefits and should be encouraged for women of all ages. Women with a history of breast cancer should not be concerned about the consumption of soy- and phytoestrogen-rich foods but should probably defer taking supplements containing isolated isoflavones.
Indole-3-carbinol (I3C).
A large body of evidence suggests that generous consumption of fruits and vegetables offers protection against numerous cancers. One group of vegetables, the cruciferous variety, may be particularly protective against breast cancer. I3C is found in high concentrations in Brassica vegetables such as broccoli, cauliflower, Brussels sprouts, kale, collards, bok choy, and cabbage. Research increasingly suggests that dietary I3C prevents the development of estrogen-enhanced cancers of the breast, endometrium, and cervix. I3C inhibits the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo.33 Exposure of various human breast cancer cell lines to I3C induces apoptosis—programmed cell death—of malignant cells.34 Whereas estrogen increases the growth and survival of tumors, I3C appears to cause growth arrest and increased apoptosis, possibly ameliorating the harmful effects of estrogen.35
Researchers are working to more fully explain the mechanism(s) by which I3C may protect against breast cancer. One area being explored is I3C’s effect on estrogen metabolism. Estrogens are metabolized via two irreversible competing pathways: 2-hydroxylation and 16-α-hydroxylation. Researchers have demonstrated that 16-α-hydroxylated metabolites have a high affinity for the estrogen receptor and low affinity for sex hormone–binding globulin, and are correlated with an increased incidence of mammary tumors in mice.36 The 2-hydroxyestrone (2-OHE) metabolite is considered less biologically active and may inhibit angiogenesis.37 These metabolites have opposing effects on estrogen receptor–positive breast cancer cells, with 16-OHE stimulating proliferation and 2-OHE showing no effect on cell growth.38
Estrogen metabolism may be altered by vegetables of the Brassica genus as a result of the presence of specific phytochemicals, indole glucosinolates. When these vegetables are cut or chewed, these phytochemicals are degraded by the plant enzyme myrosinase to a variety of indole structures.39 When broken down in the body, these indoles induce the expression of P-450 enzymes (CY1A1) in hepatic and extrahepatic tissue,40 inducing greater 2-hydroxyestrone (2HE) production and decreasing the pool of E1 available for conversion to 16-HE. In three small human interventional studies, daily administration of I3C pills (400 mg/day) or broccoli (500 g/day) significantly increased the urinary estrogen 2:16 value.41
Interestingly, no hormonal modulatory effect was seen among women with a rare mutant form of the CYP1A1 enzyme who were given oral I3C. This genetic disorder increases breast cancer risk 10-fold. This finding implies that CYP1A1 enzyme manipulation may be an important mechanism of action for I3C.42
The data have been inconsistent, however, with regard to the relationship between estrogen metabolites and breast cancer in women. One of the primary limitations is that many studies rely on measurements of estrogen metabolites made after the onset of breast cancer, which may be altered by the disease itself or by treatment.43 Only two studies collected samples prospectively from women before the onset of cancer. One revealed that breast cancer was 30% less likely to develop in postmenopausal women in the highest tertile of the ratio of urinary 2-OHE to 16-OHE over follow-up periods as long as 19 years.44 However, the number of breast cancer cases was considered too small (60 premenopausal, 42 postmenopausal) for the findings to be considered significant. The other study showed that the effect of the 2-OHE/16-OHE ratio differed with menopausal status: A low ratio was associated with a high breast cancer risk in premenopausal women but with a moderately decreased risk in postmenopausal women.45
Cigarette smoking,46 physical exercise,47 a high-protein diet,48 and consumption of cruciferous vegetables, soy,20 and omega-3 fatty acids49,50 increase the ratio of 2-OHE to 16-OHE, whereas a high–saturated fat/low–soluble fiber diet decreases it.51 Traditional lifelong Asian diets may protect against the development of breast cancer because they are rich in soy products (20% to 60% of daily protein provided by soy) and low in saturated fat.52 Potential confounders were generally not accounted for in these studies,43 making definitive conclusions about the true relationship of factors such as the ratio of 2-OHE to 16-OHE and breast cancer risk impossible at this time.
I3C may induce programmed cell death of breast cancer cells via its interaction with Bax, a cytosolic protein involved in the regulation of apoptosis. Thus I3C may be of therapeutic benefit for women with breast cancer by assisting in the regulation of the cell cycle and altering the expression of genes involved in the apoptotic pathway.53
The safety of doses up to 400 mg/day is reassuring. In a 4-week dose-ranging study, the only adverse effect noted was a slight increase in the concentration of the liver function enzyme alanine aminotransferase (which remained in the normal range) in 2 of 57 subjects.45 No subject discontinued participation. Adverse effects noted at higher dosages (800 to 1200 mg/day) included imbalance and tremor.48
Flax.
Although lignans are present in many plant foods, flax is by far the most significant source. One small study showed that daily consumption of 10 g of ground flax significantly increased the urinary 2:16 OHE-1 ratio in premenopausal women.50 The significance of this urinary-estrogen ratio, as mentioned in previous sections of this chapter, in the development of estrogen-driven cancers remains a matter of controversy.
Dietary supplements
CoQ10.
CoQ10, an antioxidant, was first isolated in 1957 from the mitochondria of beef heart and given the name ubiquinone. CoQ10 is an electron and proton carrier that assists in the production of energy (ATP) in the inner mitochondrial membrane.54 Karl Folkers first investigated CoQ10 as a treatment for cancer in the early 1970s. As an adjuvant cancer therapy, CoQ10 is thought to protect normal tissues from free-radical damage caused by conventional cancer treatment. CoQ10 has been shown to increase phagocytosis and serum immunoglobulin G levels55 while increasing resistance to bacterial, viral, and protozoal infections.56 Some studies demonstrate that patients with cancer have low levels of CoQ10.57
The medical literature contains more than 125 references to the relationship between CoQ10 and cancer, 25 involve human studies and case reports. Clinical trials addressing survival of women with breast cancer showed prolonged survival among groups receiving CoQ10; however, the studies suffered from numerous methodologic flaws (no information on disease stage, no reporting on conventional therapies used, etc.).58
Four studies of disease regression all showed a positive effect. In one clinical series of 32 women with breast cancer and lymph node involvement, all women were treated with conventional therapy and then a 6-month nutritional program including 90 mg of CoQ10, 32.5 International Units of β-carotene, 2500 International Units of vitamin E, 2850 mg of vitamin C, 387 μg of selenium, 3.5 g of omega-3 fatty acids, and 1.2 g of γ-linolenic acid per day. After 18 months no participants had died, lost weight, or needed analgesics, and all 32 reportedly had stable disease.59 The study did have its problems: 18 months is not long enough to adequately assess survival in women who underwent conventional therapy, and weight loss and the need for analgesics would only be expected in metastatic disease. Therefore, even though the results look promising, this report cannot be used as proof of efficacy. The authors published an updated report 2 years after the first follow-up.60 All the patients were alive, without evidence of metastases. Regression of cancer, including the disappearance of residual cancer after surgery in one patient taking 300 mg of CoQ10 per day, was reported in 6 patients. Other reports describe regression of liver metastases and disappearance of malignant pleural effusions.61
Survival and disease recurrence outcomes among 90 women with unilateral nonmetastatic breast cancer diagnosed between 1989 and 1998 who had been prescribed megadoses of β-carotene, vitamin C, niacin, selenium, CoQ10, and zinc in addition to standard conventional cancer therapies were compared with matched controls. Controls were matched (2:1) to the vitamin and mineral–treated patients for age at the time of diagnosis, presence of axillary lymph-node metastasis, tumor stage and grade, estrogen-receptor status, year of diagnosis, and prescription of systemic therapy. Median follow-up of surviving patients was 68 months. Breast cancer–specific survival and disease-free survival times were not improved for the vitamin and mineral–treated group over those of the controls.62
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